Conventional organic polymer hydrogels are formed by amphiphilic (hydrophilic and hydrophobic) polymers through chemical or physical interactions among the polymer molecules in aqueous solution, thereby forming a three-dimensional cross-linked net work, which absorbs water molecules into the void of the net work, affording an intermediate mechanical and physicochemical properties between the liquid and solid phases that does not flow. Hydrogels are classified into chemical hydrogels formed by chemical crosslinking among the polymer molecules having at least two functional groups and physical hydrogels formed by random physical cross-linking through hydrogen bonding, coordinate bonding, or hydrophobic interactions. A physical hydrogel is defined as a material having solid-like fluid properties and including water at equilibrium so that it is not dissolved in water (Nayak, S.; Lyon, L. A., Angew. Chem. Int. Ed. 2005, 44, 7686).
Unlike such conventional hydrogels formed by random crosslinking of amphiphilic polymers, the molecular hydrogel that is one of the most important emerging biomaterials initially developed during the last decade was reported to have a molecular weight far less than conventional polymers (Mw>10,000) and is formed by self-assembled molecular or nano-sized fibrillar networks (SAFINs), thereby absorbing a massive amount of water molecules (Weiss, R. G.; Terech, P, Molecular Gels p 1-9, Springer: Dordrecht, The Netherlands, 2006). Generally, a gel is obtained by dissolving a small amount of a gelator in a solvent (0.1-20 w/w %) and heating or cooling the solution until it does not flow. In this regard, the temperature at which the solution stops flowing is regarded as a gelation temperature (Tgel), and a minimum concentration for forming a gel is regarded as a gelation concentration (Cgel). While conventional organic polymer hydrogels have a high gelation concentration in the range of 15 to 30 w/w % of aqueous solution, molecular hydrogels have a gelation concentration of 1 w/w % or less.
A gelator is dissolved in water to form a hydrogel with a secondary structure in the range of a nanosize (10−9 m) to a microsize (10−8 m). The secondary structure is in the form of agglomerate having various shapes according to the molecular structure of the unimer, such as micellar, fibrous, ribbon-type, and plate-type. Recently, diverse researches have been conducted into behaviors of amphiphilic polymers. As described above, agglomerated particles with various shapes have been observed (Fuhrhop, J. H.; Helfrich, W. Chem. Rev. 1993, 93, 1565). Particularly, diverse research into amphiphilic polymers has been conducted with respect to gelation by crosslinking among micelles. For example, researches into a triblock copolymer including polyethylene glycol (PEG) and polypropylene glycol (PPG) (PEG-PPG-PEG) such as poloxamer (ICI) ((Jorgensen, E. B.; Havidt, S.; Brown, W.; Schillen, K. Macromolecules 1997, 30, 2355) and a diblock copolymer such as PEG-PPG (Cohn, D.; Sosnik, A.; Levy, A. Biomaterials 2003, 24, 3707) and polaxamer-polyacrylic acid (PAA) (Bromgberg, L. Langmuir 1999, 15, 6792) have been conducted.
Also, research into a gel formed by micellar aggregation has been conducted. For example, according to a result of research into a copolymer of polyethylene glycol and polyester, particularly, a triblock copolymer including polyethylene glycol-poly(lactic acid-glycolic acid)-polyethylene glycol (PEG-PLGA-PEG), the size of micelles and an aggregation number rapidly increase during sol-gel transition, and accordingly interaction between polymer molecules increases to cause a phase transition.
In addition, research into a phase transition of stimulus-sensitive hydrogels caused by diverse external stimuli such as chemical (pH) and physical (temperature and light) stimuli has been conducted. Particularly, research into thermosensitive gelling, i.e., thermogelling, has been conducted. A phase transition of polyethylene glycol-poly(lactic acid-glycolic acid)-polyethylene glycol (PEG-PLGA-PEG (550-2810-550)) in aqueous solution by thermogelling is closely related to its concentration and temperature. The phase transition occurs in the order of transparent solution>turbid solution>translucent solution>opaque gel as the temperature increases (Jeong, B.; Bae, Y. H.; Kim, S. W. Macromolecules 1999, 32, 7064). Currently, research has been conducted for wide applications of thermosensitive polymers to biomedical materials mainly used as a drug delivery system, the environment, biology, and cosmetics. For example, poly(N-isopropyl acrylamide) or polyethylene oxide copolymers, hydroxy polymers, and a few polyphosphazenes were reported to exhibit thermosensitivity (K. Park Eds, Controlled Drug Delivery, 485 (1997)). However, since most known thermosensitive polymers are toxic and are non-degradable, they were reported to be not suitable for drug delivery. Even though the copolymer of polyethylene glycol-poly(lactic acid-glycolic acid)-polyethylene glycol has biodegradability, its degraded products are acidic enough to denature protein drugs and therefore, is not suitable for protein drug delivery.
Due to high potential in various biomedical applications active researches are progressing into smart hydro-gels. Particularly, a trend of recent drug delivery systems is to apply stimulus-sensitive polymer hydro-gels to biological materials. However, most known organic polymer hydro-gels are non-biodegradable, and suitable mechanical properties (viscosity) are obtained only in a high concentration of 20 w/w % or more. Furthermore, these conventional organic polymer hydro-gels exhibit a burst effect (>30 w/w %) in the early stage when they are employed as a drug carrier for sustained drug delivery.
Meanwhile, the present inventors have found that the amphiphilic compounds prepared by grafting equimolar hydrophilic polyethylene glycol (PEG) and hydrophobic linear oligopeptide into cyclotriphosphazene forms strong spherical micelles by self-assembly in aqueous solution (Youn Soo Sohn, et al., Angew. Chem. Int. Edit. 2006, 45, 6173-6176; WO 06/043757). However, these cyclotriphosphazene micelles are thermosensitive but do not form a cross-linked network because the hydrophobic linear oligopeptide groups grafted to the cyclic phosphazene ring are efficiently oriented into the micelle core and not allowed for further hydrophobic interactions to cross-link with other micelles in aqueous solution. Instead, these amphiphilic cyclotriphosphazenes exhibit a lower critical solution temperature (LCST) at which the cyclotriphosphazene micelles precipitate due to weakened hydrogen bonding between the hydrophilic surface of the micelles and solvent water molecules when the solution temperature of the cyclotriphosphazene micelles is increased. Therefore, the cyclotriphosphazene micelles bearing linear oligopeptides do not gelate but precipitate in aqueous solution when their solution temperature is increased.